Cervical cancer is among the leading causes of cancer death worldwide. Patients often have poor access to screening and vaccination, and present in advanced stages, for which chemoradiotherapy (chemoRT) is the standard of care. This treatment is limited, however, by high rates of failure and toxicity. Although intensifying chemotherapy can improve tumor control and survival, toxicity is often unacceptably high. Strategies to reduce toxicity while increasing efficacy of chemoRT are therefore needed. Standard pelvic RT techniques encompass large volumes of normal tissue. In contrast, image-guided intensity-modulated RT (IG-IMRT) is a modern technique that maximizes target dose and minimizes normal tissue dose. Multiple studies have found that IG-IMRT can significantly reduce organ dose and reduce toxicity compared to standard RT. These studies support the hypothesis that IG-IMRT can permit delivery of more intensive chemotherapy. For example, gemcitabine, a potent radiosensitizer, has been found to improve survival for cervical cancer patients in randomized trials (Dueas-Gonzalez et al.). However, the toxicity when delivered with standard RT is extreme (>80% grade 3-4 toxicity). Therefore, this regimen has not replaced cisplatin alone as the standard of care. In contrast, our research group has found that the maximum tolerated dose of gemcitabine was increased when given with IG-IMRT. A large international multi-institutional trial has also found lower rates of toxicity with IG-IMRT compare to standard chemoRT. These findings support the hypothesis that IG-IMRT, by reducing bowel and bone marrow dose, could permit delivery of more effective concurrent chemotherapy. If confirmed, this would have significant implications for many pelvic malignancies. However, this hypothesis has not been tested in a randomized trial. CVM-1421 is an emerging NCI-funded randomized phase II trial within the NRG Oncology Cooperative Group that will test the hypothesis that adding concurrent triapine, a ribonucleotide reductase inhibitor, to concurrent cisplatin and RT can improve outcomes in patients with locoregionally advanced cervix cancer undergoing definitive chemoradiation. This trial presents a unique opportunity to study the effects of IG- IMRT on normal tissue toxicity, as it will be the first cooperative group trial to permit IG-IMRT in this population. This trial also presents an opportunity to study ways to improve IG-IMRT quality, as there has been considerable controversy in how to optimally design IG-IMRT plans, due to their increased complexity. The goal of our research is to study the effect of IG-IMRT on toxicity, quality of life, and treatment outcomes, under varying intensities of chemotherapy. We will also implement a novel technique called knowledge-based planning (KBP) in order to improve plan quality and achieve optimal IG-IMRT dose distributions. This research could help establish IG-IMRT as a new standard of care for pelvic malignancies, and will lay groundwork for future studies testing novel technologies in clinical trial settings.